Drug delivery methods and compositions that effectively provide the pharmaceutical compound at the specific site of action potentially serve to minimize toxic side effects, lower dosing requirements, and decrease therapeutic costs. The development of such systems for pulmonary drug delivery has long been a goal of the pharmaceutical industry.
Three common inhalation systems presently used to deliver drugs locally to the pulmonary air passages are dry powder inhalers (DPIs), metered dose inhalers (MDIs), and nebulizers. MDIs may be used to deliver medicaments in a solubilized form or as a dispersion. DPIs generally rely entirely on the patient's inspiratory efforts to introduce a medicament in a dry powder form to the lungs. Finally, nebulizers form a medicament aerosol to be inhaled by imparting energy to a liquid solution. While each of these methods and associated systems may prove effective in selected situations, inherent drawbacks, including formulation limitations, may limit usage.
Respiratory drug delivery places constraints on the drug particles contained within an inhaler. The drug particles generally must be in the respirable size range. A micronization process is often used in an effort to reach this size range. However, prior art powdered preparations for use in DPIs may fail to provide accurate, reproducible dosing over extended periods, in part because fine particles tend to aggregate over time, which disrupts the aerodynamic properties of the powder, thereby preventing large amounts of the aerosolized medicament from reaching the target area(s) of the lung.
One approach to overcoming this tendency toward aggregation is the use of large carrier particles (e.g. lactose) to prevent the fine drug particles from aggregating. However, substantial amounts of the drug fail to disengage from these large lactose particles and consequently deposit in the throat. As such, these carrier systems are relatively inefficient with respect to the fine particle fraction provided per actuation of the DPI.
Another solution to particle aggregation comprises making particles with relatively large geometric diameters (e.g., greater than 10 μm). Such large diameters reduce the amount and/or magnitude of particle interactions thereby preserving the flowability of the powder. The use of relatively large particles may result in dosing limitations when used in standard DPIs and provide for less than optimal dosing due to the potentially prolonged dissolution times. As such, there still remains a need for micro-sized particles that resist aggregation and preserve the flowability and dispersibility of the resulting powder.
Spray drying is an alternative manufacturing process for preparing powders for inhalation. Spray drying is a method for producing a dry powder from a liquid solution or a dispersion of particles in a liquid by drying with a hot gas. The resulting dry powders may be administered with either a DPI, or in suspension with a suitable propellant with a pMDI. Spray drying enables control of surface composition and particle morphology, factors critical in achieving good powder fluidization and dispersibility. This in turn leads to significant improvements in lung targeting and dose consistency relative to formulations based on blends of micronized API and coarse lactose monohydrate.
Forming stable suspensions of hydrophobic APIs (active pharmaceutical ingredient) in an aqueous phase can be challenging. Thermodynamically, the hydrophobic APIs want to remove contact with water. They do so by forming large flocs of drug particles. According to the literature, particle aggregation refers to formation of clusters in a colloidal suspension, and represents the most frequent mechanism leading to destabilization of colloidal systems. During this process, which normally occurs within short periods of time (seconds to hours), particles dispersed in the liquid phase stick to each other, and spontaneously form irregular particle clusters, flocs, or aggregates. This phenomenon is also referred to as coagulation or flocculation and such a suspension is also called unstable. Depending on the density of the particles and the density of the liquid medium, the particle flocs will either sediment or cream in the container. The poor stability of an aqueous-based feedstock comprising a hydrophobic drug leads to problems during spray-drying, as poor stability in the feedstock tank is reflected in variations in drug content over the batch.
Therefore, there is a need for micro-sized particulate agents (e.g., less than 10 μm) that resist aggregation and preserve the flowability and dispersibility of the resulting powder. There is also a need for methods for preparing such particulate agents. Additionally, there is a need for a process by which particles having a negligible or low solubility in water and/or particles having a lipophilic core can be prepared by spray drying a solid-in-oil emulsion.